A multifaceted chemical, biochemical, and pharmacologic research program is proposed, whose aim is the rational development of new agents against human metastatic melanoma, a tumor whose responsiveness to single agent as well as combination chemotherapy is still discouragingly low. Classes of agents that will be synthesized and studied include: (1) analogs of ara-C for use against ara-C resistant melanomas in which resistance is linked to an unfavorable ratio of kinase to deaminase activity; (2) small peptides capable of binding irreversibly to MSH receptors that are exposed on the surface of melanocytes during the G2 phase of the cell cycle; and (3) phenolic precursors of SH-reactive quinones related in structure to a natural antimelanogenic antitumor compound from the common mushroom Agaricus bisporus. A number of human and mouse melanoma sublines currently maintained in culture in our laboratory will be used to study the compounds developed in this program. This will include measurements of tyrosinase activity in pigmented and nonpigmented melanocytes, responsiveness to MSH stimulation, intracellular cytidine deaminase and cytidine kinase levels, sensitivity to various antineoplastic agents, macromolecular biosynthesis, and cell cycle parameters. In vitro studies will be complemented by appropriate in vivo assays against S91 and B16 mouse melanomas in order to select one or more promising new agents for further preclinical pharmacologic and toxicologic evaluation. An essential aspect of our proposed program is that the development of potential new agents against melanoma can proceed from the conceptual design to chemical synthesis, in vitro assay, in vivo evaluation in experimental animals, and ultimately Phase I clinical trial in a single intramural effort.